Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma

Abstract

As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

MiRNAs Mediate GDNF-Induced Proliferation and Migration of Glioma Cells

“…The GO analysis identified target genes involved in transcription regulation, signal transduction, cell adhesion, cell cycle, cell differentiation, and anti-apoptosis, all functions closely related to glioma development [38]. Recent studies have reported that precursor N-cadherin and integrin β1 proteins serve as signal transduction molecules in GDNF-induced glioma migration [13, 39]. These cell adhesion molecules are associated with 5 miRNAs, namely hsa-miR-183-5p, hsa-miR-205-5p, hsa-miR-152-3p, hsa-miR-629-5p, and hsa-miR-3609.…”

“…Notably, the increase positively correlated with pathological tumor grade [10]. Subsequent research revealed that GDNF strongly induces glioma cell proliferation and migration [11-13]. Knocking down expression of GDNF or its receptor GDNF family receptor α1 (GFRα1) effectively inhibits the pathological progression of glioma [14, 15].…”

Cross-link regulation of precursor N-cadherin and FGFR1 by GDNF increases U251MG cell viability

“…Maret et al (11) reported that the precursors of N-cadherin (proN-cadherin) and N-cadherin were present on the cell membrane and the proportion of precursors on the tumor cells was higher (11). Our previous study doubted recent studies on N-cadherin, criticizing that these studies were actually about precursors of N-cadherin, and we demonstrated that GDNF can promote the adhesion of glioma cells to the matrix by promoting the expression of proN-cadherin in glioma cells, which successively amplified the process of migration and invasion (2).…”

“…In recent years, a deeper understanding of the molecular mechanism underlying glioma development has led to the discovery of many molecular markers as indicators of clinical diagnosis and treatment. Among them are adhesion molecules involved in the migration and metastasis of gliomas (2), which are mostly clinically applied (3). However, little is known about the effect of adhesion molecules on the proliferation of tumor cells.…”

“…Cadherins are calcium-dependent cell adhesive glycoproteins which play important roles in regulating cell recognition, migration and tissue differentiation during embryonic development (4,5). N-cadherin as a classic member of cadherins is a homophilic transmembrane adhesion glycoprotein that is widely distributed in the central nervous system, especially in neurons and glial cells (2). In a variety of tumors, the abnormal expression of N-cadherin enhances cell activity and invasive ability (6) such as in breast (7), prostate (8) and bladder cancer (9).…”